The present invention relates to novel compounds which are useful in inhibiting protein isoprenyl transferases (for example, protein farnesyltransferase and protein geranylgeranyltransferase) and the farnesylation or geranylgeranylation of the oncogene protein Ras and other related small g-proteins, compositions containing such compounds and methods of using such compounds.
Ras oncogenes are the most frequently identified activated oncogenes in human tumors. Transformed protein Ras is involved in the proliferation of cancer cells. The Ras must be farnesylated before this proliferation can occur. Farnesylation of Ras by farnesyl pyrophosphate (FPP) is effected by protein farnesyltransferase. Inhibition of protein farnesyltransferase, and thereby farnesylation of the Ras protein, blocks the ability of transformed cells to proliferate. Inhibition of protein geranylgeranyltransferase and, thereby, of geranylgeranylation of Ras proteins, also results in down regulation of Ras protein function.
Activation of Ras and other related small g-proteins that are farnesylated and/or geranylated also partially mediates smooth muscle cell proliferation (Circulation, I-3: 88 (1993), which is hereby incorporated herein by reference). Inhibition of protein isoprenyl transferases, and thereby farnesylation or geranylgeranylation of the Ras protein, also aids in the prevention of intimal hyperplasia associated with restenosis and atherosclerosis, a condition which compromises the success of angioplasty and surgical bypass for obstructive vascular lesions.
There is therefore a need for compounds which are inhibitors of protein farnesyltransferase and protein geranylgeranyltransferase.
In its principle embodiment, the invention provides a compound having the formula: 
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of
(1) hydrogen,
(2) alkenyl,
(3) alkynyl,
(4) alkoxy,
(5) haloalkyl,
(6) halogen,
(7) loweralkyl,
(8) thioalkoxy,
(9) aryl-L2xe2x80x94 wherein aryl is selected from the group consisting of
(a) phenyl,
(b) naphthyl,
(c) dihydronaphthyl,
(d) tetrahydronaphthyl,
(e) indanyl, and
(f) indenyl
wherein (a)-(f) are unsubstituted or substituted with at least one of X, Y, or Z wherein X, Y, and Z are independently selected from the group consisting of
alkenyl,
alkynyl,
alkoxy,
aryl,
aryloxy,
carboxy,
cyano,
halogen,
haloalkyl,
hydroxy,
hydroxyalkyl,
loweralkyl,
nitro,
N-protected amino, and
xe2x80x94NRRxe2x80x2 wherein R and Rxe2x80x2 are independently selected from the group consisting of
hydrogen and
loweralkyl,
oxo (xe2x95x90O), and
thioalkoxy and
L2 is absent or is selected from the group consisting of
xe2x80x94CH2xe2x80x94,
xe2x80x94CH2CH2xe2x80x94,
xe2x80x94CH(CH3)xe2x80x94,
xe2x80x94C(O)xe2x80x94,
S(O)q wherein q is 0, 1 or 2, and
xe2x80x94N(R)xe2x80x94, and
(10) heterocycle-L2xe2x80x94 wherein L2 is as defined above and the heterocycle is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of
(a) loweralkyl,
(b) hydroxy,
(c) hydroxyalkyl,
(d) halogen
(e) cyano,
(f) nitro,
(g) oxo (xe2x95x90O),
(h) xe2x80x94NRRxe2x80x2,
(i) N-protected amino,
(j) alkoxy,
(k) thioalkoxy,
(l) haloalkyl,
(m) carboxy, and
(n) aryl;
R2 is selected from the group consisting of
(1) 
xe2x80x83wherein L11 is selected from the group consisting of
(a) a covalent bond,
(b) xe2x80x94C(W)N(R)xe2x80x94 wherein R is defined previously and W is selected from the group consisting of O and S,
(c) xe2x80x94C(O)xe2x80x94,
(d) xe2x80x94N(R)C(W)xe2x80x94,
(e) xe2x80x94CH2Oxe2x80x94,
(f) xe2x80x94C(O)Oxe2x80x94, and
(g) xe2x80x94CH2N(R)xe2x80x94,
R12a is selected from the group consisting of
(a) hydrogen,
(b) loweralkyl, and
(c) xe2x80x94C(O)OR13 wherein R13 is selected from the group consisting of
hydrogen and
a carboxy-protecting group, and
R12b is selected from the group consisting of
(a) hydrogen and
(b) loweralkyl,
with the proviso that R12a and R12b are not both hydrogen,
(2) xe2x80x94L11xe2x80x94C(R14)(Rv)xe2x80x94C(O)OR15 wherein L11 is defined previously, Rv is selected from the group consisting of
(a) hydrogen and
(b) loweralkyl,
R15 is selected from the group consisting of
(a) hydrogen,
(b) alkanoyloxyalkyl,
(c) loweralkyl, and
(b) a carboxy-protecting group, and
R14 is selected from the group consisting of
(a) alkoxyalkyl,
(b) alkoxyarylalkyl,
(c) alkoxycarbonylalkyl,
(d) alkylsulfinyalkyl,
(e) alkylsulfonylalkyl,
(f) alkynyl,
(g) aminoalkyl,
(h) aminocarbonylalkyl,
(i) aminothiocarbonylalkyl,
(j) aryl,
(k) arylalklyl,
(l) carboxyalkyl,
(m) cyanoalkyl,
(n) cycloalkyl,
(o) cycloalkylalkoxyalkyl,
(p) cycloalkylalkyl,
(q) (heterocyclic)alkyl,
(r) hydroxyalkyl,
(s) hydroxyarylalkyl,
(t) loweralkyl,
(u) sulfhydrylalkyl,
(v) thioalkoxyalkyl wherein the thioalkoxyalkyl is unsubstituted or substituted with 1, 2, 3, or 4 substituents selected from the group consisting of
halogen,
(w) thioalkoxyalkylamino, and
(x) thiocycloalkyloxyalkyl, 
xe2x80x83wherein n is 1-3,
(4) xe2x80x94C(O)NHxe2x80x94CH(R14)xe2x80x94C(O)NHSO2R16 wherein R14 is defined previously and R16 is selected from the group consisting of
(a) loweralkyl,
(b) haloalkyl,
(c) aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
loweralkyl,
hydroxy,
hydroxyalkyl,
halogen,
cyano,
nitro,
oxo (xe2x95x90O),
xe2x80x94NRRxe2x80x2
N-protected amino,
alkoxy,
thioalkoxy,
haloalkyl,
carboxy, and
aryl, and
(d) heterocycle wherein the heterocycle is unsubstituted or substituted with substituents independently selected from the group consisting of
loweralkyl,
hydroxy,
hydroxyalkyl,
halogen,
cyano,
nitro,
oxo (xe2x95x90O),
xe2x80x94NRRxe2x80x2,
N-protected amino,
alkoxy,
thioalkoxy,
haloalkyl,
carboxy, and
aryl;
(5) xe2x80x94C(O)NHxe2x80x94CH(R14)-tetrazolyl wherein the tetrazole ring is unsubstituted or substituted with loweralkyl or haloalkyl,
(6) xe2x80x94L11-heterocycle,
(7) C(O)NHxe2x80x94CH(R14)xe2x80x94C(O)NR17R18 wherein R14 is defined previously and R17 and R18 are independently selected from the group consisting of
(a) hydrogen,
(b) loweralkyl,
(c) arylalkyl,
(d) hydroxy, and
(e) dialkylaminoalkyl,
(8) C(O)OR15, and
(9) C(O)NHxe2x80x94CH(R14)-heterocycle wherein R14 is as previously defined and the heterocycle is unsubstituted or substituted with loweralkyl or haloalkyl;
L1 is absent or is selected from the group consisting of
xe2x80x94L4xe2x80x94N(R5)xe2x80x94L5xe2x80x94 wherein L4 is absent or selected from the group consisting of
(a) C1-to-C10-alkylene and
(b) C2-to-C16-alkenylene,
wherein the alkylene and alkenylene groups are unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from the group consisting of
alkenyl,
alkenyloxy,
alkenyloxyalkyl,
alkenyl[S(O)q]alkyl,
alkoxy,
alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2 hydroxyl substituents,
with the proviso that no two hydroxyls are attached to the same carbon,
alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of
halogen and
cycloalkyl,
alkylsilyloxy,
alkyl[S(O)q],
alkyl[S(O)q]alkyl,
aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
alkoxy wherein the alkoxy is unsubstituted or substituted with substituents selected from the group consisting of cycloalkyl,
aryl,
arylalkyl,
aryloxy wherein the aryloxy is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of,
xe2x80x83halogen,
xe2x80x83nitro, and
xe2x80x83xe2x80x94NRRxe2x80x2,
cycloalkyl,
halogen,
loweralkyl,
hydroxyl,
nitro,
xe2x80x94NRRxe2x80x2, and
xe2x80x94SO2NRRxe2x80x2,
arylalkoxy wherein the arylalkoxy is unsubstituted or substituted with substituents selected from the group consisting of alkoxy,
arylalkyl,
arylalkyl[S(O)q]alkyl,
aryl[S(O)q],
aryl[S(O)q]alkyl wherein the aryl[S(O)q]alkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from alkoxy and loweralkyl,
arylalkoxyalkyl wherein the arylalkoxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of
alkoxy, and
halogen,
aryloxy,
aryloxyalkyl wherein the aryloxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of halogen,
carboxyl,
xe2x80x94C(O)NRCRD wherein RC and RD are independently selected from the group consisting of
hydrogen,
loweralkyl, and
alkoxycarbonyl or
RC and RD together with the nitrogen to which they are attached form a ring selected from the group consisting of
xe2x80x83morpholine,
xe2x80x83piperidine,
xe2x80x83pyrrolidine
xe2x80x83thiomorpholine,
xe2x80x83thiomorpholine sulfone, and
xe2x80x83thiomorpholine sulfoxide,
xe2x80x83wherein the ring formed by RC and RD together is unsubstituted or
xe2x80x83substituted with 1 or 2 substituents independently selected from the group consisting of alkoxy and alkoxyalkyl,
cycloalkenyl wherein the cycloalkenyl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of alkenyl,
cyclolalkoxy,
cycloalkoxycarbonyl,
cyclolalkoxyalkyl,
cyclolalkyl wherein the cycloalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of aryl, loweralkyl, and alkanoyl,
cycloalkylalkoxy,
cycloalkylalkoxycarbonyl,
cycloalkylalkoxyalkyl,
cycloalkylalkyl,
cyclolalkyl[S(O)q]alkyl,
cycloalkylalkyl[S(O)q]alkyl,
fluorenyl,
heterocycle wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of
alkoxy wherein the alkoxy is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of aryl and cycloalkyl,
alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of
xe2x80x83aryl and
xe2x80x83cycloalkyl,
alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of
xe2x80x83aryl and
xe2x80x83cycloalkyl,
aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
xe2x80x83alkanoyl,
xe2x80x83alkoxy,
xe2x80x83carboxaldehyde,
xe2x80x83haloalkyl,
xe2x80x83halogen,
xe2x80x83loweralkyl,
xe2x80x83nitro,
xe2x80x83xe2x80x94NRRxe2x80x2, and
xe2x80x83thioalkoxy,
arylalkyl,
aryloxy,
cycloalkoxyalkyl,
cycloalkyl,
cycloalkylalkyl,
halogen,
heterocycle,
hydroxyl,
loweralkyl wherein the loweralkyl is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of
xe2x80x83heterocycle,
xe2x80x83hydroxyl,
xe2x80x83with the proviso that no two hydroxyls are attached to the same carbon, and
xe2x80x83xe2x80x94NRR3R3xe2x80x2 wherein RR3 and RR3xe2x80x2 are independently selected from the group consisting of
xe2x80x83hydrogen
xe2x80x83aryl,
xe2x80x83loweralkyl,
xe2x80x83aryl,
xe2x80x83arylalkyl,
xe2x80x83heterocycle,
xe2x80x83(heterocyclic)alkyl,
xe2x80x83cycloalkyl, and
xe2x80x83cycloalkylalkyl, and
xe2x80x83sulfhydryl,
(heterocyclic)alkoxy,
(heterocyclic)alkyl,
(heterocyclic)alkyl[S(O)q]alkyl,
(heterocyclic)oxy,
(heterocyclic)alkoxyalkyl,
(heterocyclic)oxyalkyl,
heterocycle[S(O)q]alkyl,
hydroxyl,
hydroxyalkyl,
imino,
N-protected amino,
xe2x95x90Nxe2x80x94O-aryl, and
xe2x95x90Nxe2x80x94OH,
xe2x95x90Nxe2x80x94O-heterocycle wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of
xe2x80x83loweralkyl,
xe2x80x83hydroxy,
xe2x80x83hydroxyalkyl,
xe2x80x83halogen,
xe2x80x83cyano,
xe2x80x83nitro,
xe2x80x83oxo (xe2x95x90O),
xe2x80x83xe2x80x94NRRxe2x80x2
xe2x80x83N-protected amino,
xe2x80x83alkoxy,
xe2x80x83thioalkoxy,
xe2x80x83haloalkyl,
xe2x80x83carboxy, and
xe2x80x83aryl,
xe2x95x90Nxe2x80x94O-loweralkyl,
xe2x80x94NRR3RR3xe2x80x2,
xe2x80x94NHNRCRD,
xe2x80x94OG wherein G is a hydroxyl protecting group,
xe2x80x94Oxe2x80x94NHxe2x80x94R, 
xe2x80x83wherein J and Jxe2x80x2 are independently selected from the group consisting of
xe2x80x83loweralkyl and
xe2x80x83arylalkyl,
oxo,
oxyamino(alkyl)carbonylalkyl,
oxyamino(arylalkyl)carbonylalkyl,
oxyaminocarbonylalkyl,
xe2x80x94SO2xe2x80x94A wherein A is selected from the group consisting of
xe2x80x83loweralkyl,
xe2x80x83aryl, and
xe2x80x83heterocycle
xe2x80x83wherein the loweralkyl, aryl, and heterocycle are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
xe2x80x83alkoxy,
xe2x80x83halogen,
xe2x80x83haloalkyl,
xe2x80x83loweralkyl, and
xe2x80x83nitro,
sulfhydryl,
thioxo, and
thioalkoxy,
L5 is absent or selected from the group consisting of
(a) C1-to-C10-alkylene and
(b) C2-to-C16-alkenylene
wherein (a) and (b) are unsubstituted or substituted as defined previously, and
R5 is selected from the group consisting of
hydrogen,
alkanoyl wherein the alkanoyl is unsubstituted or substituted with substituents selected from the group consisting of aryl,
alkoxy,
alkoxyalkyl,
alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of
aryl and
halogen,
alkylaminocarbonylalkyl wherein the alkylaminocarbonylalkyl is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of aryl,
(anthracenyl)alkyl,
aryl,
arylalkoxy,
arylalkyl wherein the arylalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
alkoxy,
aryl,
carboxyl,
cyano,
halogen,
haloalkoxy,
haloalkyl,
nitro,
oxo, and
xe2x80x94L11xe2x80x94C(R14)(Rv)xe2x80x94C(O)OR15,
(aryl)oyl wherein the (aryl)oyl is unsubstituted or substituted with substituents selected from the group consisting of halogen,
aryloxycarbonyl,
carboxaldehyde,
xe2x80x94C(O)NRRxe2x80x2,
cycloalkoxycarbonyl,
cycloalkylaminocarbonyl,
cycloalkylaminothiocarbonyl,
cyanoalkyl,
cyclolalkyl,
cycloalkylalkyl wherein the cycloalkylalkyl is unsubstituted or substituted with 1 or 2 hydroxyl substituents,
with the proviso that no two hydroxyls are attached to the same carbon,
(cyclolalkyl)oyl,
(9,10-dihydroanthracenyl)alkyl wherein the (9,10-dihydroanthracenyl)alkyl is unsubstituted or substituted with 1 or 2 oxo substituents,
haloalkyl,
heterocycle,
(heterocyclic)alkyl wherein the (heterocyclic)alkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of
loweralkyl,
(heterocyclic)oyl,
loweralkyl, wherein the loweralkyl is unsubstituted or substituted with substituents selected from the group consisting of xe2x80x94NRRxe2x80x2,
xe2x80x94SO2xe2x80x94A, and
thioalkoxyalkyl;
(2) xe2x80x94L4xe2x80x94Oxe2x80x94L5xe2x80x94,
(3) xe2x80x94L4xe2x80x94S(O)mxe2x80x94L5xe2x80x94 wherein L4 and L5 are defined previously and m is 0, 1, or 2,
(4) xe2x80x94L4xe2x80x94L6xe2x80x94C(W)xe2x80x94N(R4xe2x80x2)xe2x80x94L5xe2x80x94 wherein L4, W, and L5 are defined previously, and R4xe2x80x2 is selected from the group consisting of
(a) hydrogen,
(b) loweralkyl,
(c) aryl,
(d) arylalkyl,
(e) heterocycle,
(f) (heterocyclic)alkyl,
(g) cyclolakyl, and
(h) cycloalkylalkyl, and
L6 is absent or is selected from the group consisting of
(a) xe2x80x94Oxe2x80x94,
(b) xe2x80x94Sxe2x80x94, and
(c) xe2x80x94N(R4xe2x80x2)xe2x80x94 wherein R4xe2x80x2 is selected from the group consisting of
hydrogen,
loweralkyl,
aryl,
arylalkyl,
heterocycle,
(heterocyclic)alkyl,
cyclolakyl, and
cycloalkylalkyl,
(5) xe2x80x94L4xe2x80x94L6xe2x80x94S(O)mxe2x80x94N(R7)xe2x80x94L5xe2x80x94,
(6) xe2x80x94L4xe2x80x94L6xe2x80x94N(R5)xe2x80x94S(O)mxe2x80x94L5xe2x80x94,
(7) xe2x80x94L4xe2x80x94N(R5)xe2x80x94C(W)xe2x80x94L7xe2x80x94L5xe2x80x94 wherein L4, R5, W, and L5 are defined previously and L7 is absent or is selected from the group consisting of xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94,
(8) C1-C10-alkylene wherein the alkylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of
(a) aryl,
(b) arylalkyl,
(c) heterocycle,
(d) (heterocyclic)alkyl,
(e) cyclolakyl,
(f) cycloalkylalkyl,
(g) alkylthioalkyl, and
(h) hydroxy,
(9) C2-to-C10-alkenylene wherein the alkenylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of
(a) aryl,
(b) arylalkyl,
(c) (aryl)oxyalkyl wherein the (aryl)oxyalkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of halogen,
(d) heterocycle,
(e) (hererocycle)alkyl,
(f) hydroxyalkyl,
(g) cyclolakyl,
(h) cycloalkylalkyl,
(i) alkylthioalkyl, and
(l) hydroxy,
(10) C2-to-C10-alkynylene wherein the alkynylene group is unsubstituted or substituted with 1 or 2 substituents independently selected from the group consisting of
(a) aryl,
(b) arylalkyl,
(c) heterocycle,
(d) (heterocyclic)alkyl,
(e) cyclolakyl,
(f) cycloalkylalkyl,
(g) alkylthioalkyl, and
(h) hydroxy,
(11) xe2x80x94L4-heterocycle-L5xe2x80x94,
(12) a covalent bond,
(13) 
xe2x80x83wherein B is selected from the group consisting of loweralkyl and arylalkyl, and
(14) 
Z is selected from the group consisting of
(1) a covalent bond,
(2) xe2x80x94Oxe2x80x94,
(3) S(O)qxe2x80x94, and
(4) xe2x80x94NRzxe2x80x94 wherein Rz is selected from the group consisting of
(a) hydrogen,
(b) loweralkyl,
(c) aryl,
(d) arylalkyl,
(e) heterocycle,
(f) (heterocyclic)alkyl,
(g) cyclolakyl, and
(h) cycloalkylalkyl;
R3 is selected from the group consisting of
(1) pyridyl and
(2) imidazolyl
wherein the pyridyl or imidazolyl are unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
(a) alkanoyl,
(b) alkoxy wherein the alkoxy is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
halogen,
aryl, and
cycloalkyl,
(c) alkoxyalkyl wherein the alkoxyalkyl is unsubstituted or substituted with 1 or 2, 3, 4 or 5 substituents independently selected from the group consisting of
aryl and
cycloalkyl,
(d) alkoxycarbonyl wherein the alkoxycarbonyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
aryl, and
cycloalkyl,
(e) alkylsilyloxyalkyl,
(f) arylalkyl,
(g) aryl wherein the aryl is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
alkanoyl,
alkoxy wherein the alkoxy is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of cycloalkyl,
carboxaldehyde,
haloalkyl,
halogen,
loweralkyl,
nitro,
xe2x80x94NRRxe2x80x2, and
thioalkoxy,
(h) arylalkyl,
(i) aryloxy wherein the aryloxy is unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of,
halogen,
nitro, and
xe2x80x94NRRxe2x80x2,
(j) (aryl)oyl,
(k) carboxaldehyde,
(l) carboxy,
(m) carboxyalkyl,
(n) xe2x80x94C(O)NRRxe2x80x3 wherein R is defined previously and Rxe2x80x3 is selected from the group consisting of
hydrogen,
loweralkyl, and
carboxyalkyl,
(o) cyano,
(p) cyanoalkyl,
(q) cycloalkyl,
(r) cycloalkylalkyl,
(s) cycloalkoxyalkyl,
(t) halogen,
(u) haloalkyl wherein the haloalkyl is unsubstitute or substituted
with 1, 2, 3, 4, or 5 hydroxyl substituents, with the proviso that no two hydroxyls are attached to the same carbon,
(v) heterocycle,
(w) hydroxyl,
(x) hydroxyalkyl wherein the hydroxyalkyl is unsubstituted or substituted with substituents selected from the group consisting of aryl,
(y) loweralkyl wherein the loweralkyl is unsubstituted or substituted with substituents selected from the group consisting of
heterocycle,
hydroxyl,
with the proviso that no two hydroxyls are attached to the same carbon,
xe2x80x94NRR3RR3xe2x80x2, and
xe2x80x94P(O)(OR)(ORxe2x80x2),
(z) nitro,
(aa) xe2x80x94NRRxe2x80x2,
(bb) oxo,
(cc) xe2x80x94SO2NRAxe2x80x2RBxe2x80x2 wherein RAxe2x80x2 and RBxe2x80x2 are independently selected from the group consisting of
hydrogen,
(aryl)oyl,
loweralkyl, and
heterocycle wherein the heterocycle is unsubstituted or substituted with 1, 2, or 3 substituents independently selected from the group consisting of loweralkyl,
(dd) sulfhydryl, and
(ee) thioalkoxy;
R4 is selected from the group consisting of
(1) hydrogen,
(2) loweralkyl,
(3) haloalkyl
(4) halogen,
(5) aryl,
(6) arylalkyl,
(7) heterocycle,
(8) (heterocyclic)alkyl,
(9) alkoxy, and
(10) xe2x80x94NRRxe2x80x2; or
L1, Z, and R3 together are selected from the group consisting of
(1) aminoalkyl,
(1) haloalkyl,
(2) halogen,
(3) carboxaldehyde,
(4) (carboxaldehyde)alkyl, and
(5) hydroxyalkyl,
with the proviso that when L1, Z, and R3 together are (1)-(5), R1 is other than hydrogen, or
L1, Z, R3, and R4 together are a pyrrolidinone ring wherein the pyrrolidinone ring is unsubstituted or substituted with heterocycle.
In a further aspect of the present invention are disclosed pharmaceutical compositions which comprise a compound of formula I in combination with a pharmaceutically acceptable carrier.
In yet another aspect of the present invention are disclosed pharmaceutical compositions which comprise a compound of formula I in combination with another chemotherapeutic agent and a pharmaceutically acceptable carrier.
In yet another aspect of the present invention is disclosed a method for inhibiting protein isoprenyl transferases (i.e., protein farnesyltransferase and/or geranylgeranyltransferase) in a human or lower mammal, comprising administering to the patient a therapeutically effective amount of a compound of formula I.
In yet another aspect of the present invention is disclosed a method for inhibiting post-translational modification of the oncogenic Ras protein by protein farnesyltransferase, protein geranylgeranyltransferase or both.
In yet another aspect of the present invention is disclosed a method for treatment of conditions mediated by farnesylated or geranylgeranylated proteins, for example, treatment of Ras associated tumors in humans and other mammals.
In yet another aspect of the present invention is disclosed a method for inhibiting or treating cancer in a human or lower mammal comprising administering to the patient a therapeutically effective amount of a compound of the invention alone or in combination with another chemotherapeutic agent.
In yet another aspect of the present invention is disclosed a method for treating or preventing intimal hyperplasia associated with restenosis and atherosclerosis in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
The compounds of the invention can comprise asymmetrically substituted carbon atoms. As a result, all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention. The terms xe2x80x9cSxe2x80x9d and xe2x80x9cRxe2x80x9d configuration, as used herein, are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13-30, which is hereby incorporated herein by reference.
As used herein the terms xe2x80x9cCys,xe2x80x9d xe2x80x9cGlu,xe2x80x9d xe2x80x9cLeu,xe2x80x9d xe2x80x9cLys,xe2x80x9d xe2x80x9cMet,xe2x80x9d xe2x80x9cnor-Leu,xe2x80x9d xe2x80x9cnor-Val,xe2x80x9d xe2x80x9cPhe,xe2x80x9d xe2x80x9cSerxe2x80x9d and xe2x80x9cValxe2x80x9d refer to cysteine, glutamine, leucine, lysine, methionine, norleucine, norvaline, phenylalanine, serine and valine in their L-, D- or DL forms. As used herein these amino acids are in their naturally occurring L-form.
As used herein, the term xe2x80x9ccarboxy protecting groupxe2x80x9d refers to a carboxylic acid protecting ester group employed to block or protect the carboxylic acid functionality while the reactions involving other functional sites of the compound are carried out. Carboxy protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d pp. 152-186 (1981), which is hereby incorporated herein by reference. In addition, a carboxy protecting group can be used as a prodrug whereby the carboxy protecting group can be readily cleaved in vivo (for example by enzymatic hydrolysis) to release the biologically active parent. T. Higuchi and V. Stella provide a thorough discussion of the prodrug concept in xe2x80x9cPro-drugs as Novel Delivery Systemsxe2x80x9d, Vol 14 of the A.C.S. Symposium Series, American Chemical Society (1975), which is hereby incorporated herein by reference. Such carboxy protecting groups are well known to those skilled in the art, having been extensively used in the protection of carboxyl groups in the penicillin and cephalosporin fields (as described in U.S. Pat. Nos. 3,840,556 and 3,719,667, the disclosures of which are hereby incorporated herein by reference). Examples of esters useful as prodrugs for compounds containing carboxyl groups can be found on pages 14-21 of xe2x80x9cBioreversible Carriers in Drug Design: Theory and Applicationxe2x80x9d, edited by E. B. Roche, Pergamon Press, New York (1987), which is hereby incorporated herein by reference.
Representative carboxy protecting groups are C1 to C8 loweralkyl (e.g., methyl, ethyl or tertiary butyl and the like); arylalkyl, for example, phenethyl or benzyl and substituted derivatives thereof such as alkoxybenzyl or nitrobenzyl groups and the like; arylalkenyl, for example, phenylethenyl and the like; aryl and substituted derivatives thereof, for example, 5-indanyl and the like; dialkylaminoalkyl (e.g., dimethylaminoethyl and the like); alkanoyloxyalkyl groups such as acetoxymethyl, butyryloxymethyl, valeryloxymethyl, isobutyryloxymethyl, isovaleryloxymethyl, 1-(propionyloxy)-1-ethyl, 1-(pivaloyloxyl)-1-ethyl, 1-methyl-1-(propionyloxy)-1-ethyl, pivaloyloxymethyl, propionyloxymethyl and the like; cycloalkanoyloxyalkyl groups such as cyclopropylcarbonyloxymethyl, cyclobutylcarbonyloxymethyl, cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl and the like; aroyloxyalkyl, such as benzoyloxymethyl, benzoyloxyethyl and the like; arylalkylcarbonyloxyalkyl, such as benzylcarbonyloxymethyl, 2-benzylcarbonyloxyethyl and the like; alkoxycarbonylalkyl or cycloalkyloxycarbonylalkyl, such as methoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 1-methoxycarbonyl-1-ethyl, and the like; alkoxycarbonyloxyalkyl or cycloalkyloxycarbonyloxyalkyl, such as methoxycarbonyloxymethyl, t-butyloxycarbonyloxymethyl, 1-ethoxycarbonyloxy-1-ethyl, 1-cyclohexyloxycarbonyloxy-1-ethyl and the like; aryloxycarbonyloxyalkyl, such as 2-(phenoxycarbonyloxy)ethyl, 2-(5-indanyloxycarbonyloxy)ethyl and the like; alkoxyalkylcarbonyloxyalkyl, such as 2-(1-methoxy-2-methylpropan-2-oyloxy)ethyl and like; arylalkyloxycarbonyloxyalkyl, such as 2-(benzyloxycarbonyloxy)ethyl and the like; arylalkenyloxycarbonyloxyalkyl, such as 2-(3-phenylpropen-2-yloxycarbonyloxy)ethyl and the like; alkoxycarbonylaminoalkyl, such as t-butyloxycarbonylaminomethyl and the like; alkylaminocarbonylaminoalkyl, such as methylaminocarbonylaminomethyl and the like; alkanoylaminoalkyl, such as acetylaminomethyl and the like; heterocycliccarbonyloxyalkyl, such as 4-methylpiperazinylcarbonyloxymethyl and the like; dialkylaminocarbonylalkyl, such as dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl and the like; (5-(loweralkyl)-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-t-butyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like; and (5-phenyl-2-oxo-1,3-dioxolen-4-yl)alkyl, such as (5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl and the like.
Preferred carboxy-protected compounds of the invention are compounds wherein the protected carboxy group is a loweralkyl, cycloalkyl or arylalkyl ester, for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, sec-butyl ester, isobutyl ester, amyl ester, isoamyl ester, octyl ester, cyclohexyl ester, phenylethyl ester and the like or an alkanoyloxyalkyl, cycloalkanoyloxyalkyl, aroyloxyalkyl or an arylalkylcarbonyloxyalkyl ester.
The term xe2x80x9cN-protecting groupxe2x80x9d or xe2x80x9cN-protectedxe2x80x9d as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d (John Wiley and Sons, New York (1981)), which is hereby incorporated herein by reference. N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, t-benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term xe2x80x9calkanoylxe2x80x9d as used herein refers to R29C(O)xe2x80x94 wherein R29 is a loweralkyl group. The alkanoyl groups of this invention can be optionally substituted.
The term xe2x80x9calkanoylaminoalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R71xe2x80x94NHxe2x80x94 wherein R71 is an alkanoyl group. The alkanoylaminoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkanoyloxyxe2x80x9d as used herein refers to R29C(O)xe2x80x94Oxe2x80x94 wherein R29 is a loweralkyl group. The alkanoyloxy groups of this invention can be optionally substituted.
The term xe2x80x9calkanoyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an alkanoyloxy group. The alkanoyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkenylxe2x80x9d as used herein refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenyl include xe2x80x94CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3, and the like. The alkenyl groups of this invention can be optionally substituted.
The term xe2x80x9calkenylenexe2x80x9d as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 20 carbon atoms and also containing at least one carbon-carbon double bond. Examples of alkenylene include xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHxe2x80x94, xe2x80x94C(CH3)xe2x95x90CHxe2x80x94, xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94, and the like. The alkenylene groups of this invention can be optionally substituted.
The term xe2x80x9calkenyloxyxe2x80x9d as used herein refers to an alkenyl group attached to the parent molecular group through an oxygen atom. The alkenyloxy groups of this invention can be optionally substituted.
The term xe2x80x9calkenyloxyalkylxe2x80x9d as used herein refers to a loweralkyl group to which is attached an alkenyloxy group. The alkenyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkoxyxe2x80x9d as used herein refers to R30Oxe2x80x94 wherein R30 is loweralkyl as defined above. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy and the like. The alkoxy groups of this invention can be optionally substituted.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to a loweralkyl group to which is attached an alkoxy group. The alkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkoxyalkoxyxe2x80x9d as used herein refers to R31Oxe2x80x94R32Oxe2x80x94 wherein R31 is loweralkyl as defined above and R32 is an alkylene radical. Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like. The alkoxyalkoxy groups of this invention can be optionally substituted.
The term xe2x80x9calkoxyalkylxe2x80x9d as used herein refers to an alkoxy group as previously defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like. The alkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkoxyalkylcarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R66xe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R66 is an alkoxyalkyl group.
The term xe2x80x9calkoxyarylalkylxe2x80x9d as used herein refers to a an arylalkyl group to which is attached an alkoxy group. The alkoxyarylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein refers to an alkoxy group as previously defined appended to the parent molecular moiety through a carbonyl group. Examples of alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl and the like. The alkoxycarbonyl groups of this invention can be optionally substituted. The alkoxycarbonyl groups of this invention can be optionally substituted.
The term xe2x80x9calkoxycarbonylalkylxe2x80x9d as used herein refers to an alkoxylcarbonyl group as previously defined appended to a loweralkyl radical. Examples of alkoxycarbonylalkyl include methoxycarbonylmethyl, 2-ethoxycarbonylethyl and the like. The alkoxycarbonylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkoxycarbonylaminoalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R69xe2x80x94NHxe2x80x94 wherein R69 is an alkoxycarbonyl group. The alkoxycarbonylaminoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkoxycarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R63xe2x80x94Oxe2x80x94 wherein R63 is an alkoxycarbonyl group. The alkoxycarbonyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkylaminoxe2x80x9d as used herein refers to R35NHxe2x80x94 wherein R35 is a loweralkyl group, for example, methylamino, ethylamino, butylamino, and the like. The alkylamino groups of this invention can be optionally substituted.
The term xe2x80x9calkylaminoalkylxe2x80x9d as used herein refers a loweralkyl radical to which is appended an alkylamino group. The alkylaminoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkylaminocarbonylaminoalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R70xe2x80x94C(O)xe2x80x94NHxe2x80x94 wherein R70 is an alkylamino group. The alkylaminocarbonylaminoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkylenexe2x80x9d as used herein refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 10 carbon atoms by the removal of two hydrogen atoms, for example methylene, 1,2-ethylene, 1,1-ethylene, 1,3-propylene, 2,2-dimethylpropylene, and the like. The alkylene groups of this invention can be optionally substituted.
The term xe2x80x9calkylsilyloxyxe2x80x9d as used herein refers to a loweralkyl group to which is attached xe2x80x94OSiRWxe2x80x2RXxe2x80x2RYxe2x80x2 wherein RWxe2x80x2, RXxe2x80x2, and RYxe2x80x2 are selected from the group consisting of loweralkyl.
The term xe2x80x9calkylsulfinylxe2x80x9d as used herein refers to R33S(O)xe2x80x94 wherein R33 is a loweralkyl group. The alkylsulfinyl groups of this invention can be optionally substituted.
The term xe2x80x9calkylsulfinylalkylxe2x80x9d as used herein refers to an alkyl group to which is attached a alkylsulfinyl group. The alkylsulfinylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkylsulfonylxe2x80x9d as used herein refers to R34S(O)2xe2x80x94 wherein R34 is a loweralkyl group. The alkylsulfonyl groups of this invention can be optionally substituted.
The term xe2x80x9calkylsulfonylalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an alkylsulfonyl group. The alkylsulfonylalkyl groups of this invention can be optionally substituted.
The term alkylthioalkyl as used herein refers to a lower alkyl group as defined herein attached to the parent molecular moiety through a sulfur atom and an alkylene group. The alkylthioalkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkynylxe2x80x9d as used herein refers to a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynyl include xe2x80x94Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1CH, xe2x80x94CH2Cxe2x89xa1CH3, and the like. The alkynyl groups of this invention can be optionally substituted.
The term xe2x80x9calkynylenexe2x80x9d as used herein refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon triple bond. Examples of alkynylene include xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2Cxe2x89xa1Cxe2x80x94, xe2x80x94CH2Cxe2x89xa1CCH2xe2x80x94, and the like. The alkynylene groups of this invention can be optionally substituted.
The term xe2x80x9caminoxe2x80x9d as used herein refers to xe2x80x94NH2.
The term xe2x80x9caminocarbonylxe2x80x9d as used herein refers to an amino group attached to the parent molecular group through a carbonyl group. The aminocarbonyl groups of this invention can be optionally substituted.
The term xe2x80x9caminocarbonylalkylxe2x80x9d as used herein refers to an alkyl group to which is attached an aminocarbonyl group. The aminocarbonylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9caminoalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an amino group. The aminoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9caminothiocarbonylxe2x80x9d as used herein refers to an amino group attached to the parent molecular group through a thiocarbonylcarbonyl (Cxe2x95x90S) group. The aminothiocarbonyl groups of this invention can be optionally substituted.
The term xe2x80x9caroyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an aroyloxy group (i.e., R61xe2x80x94C(O)Oxe2x80x94 wherein R61 is an aryl group). The aroyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9carylxe2x80x9d as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, sulfhydryl, nitro, cyano, carboxaldehyde, carboxy, alkoxycarbonyl, haloalkyl-C(O)xe2x80x94NHxe2x80x94, haloalkenyl-C(O)xe2x80x94NHxe2x80x94 and carboxamide. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.
The term xe2x80x9carylalkenylxe2x80x9d as used herein refers to an alkenyl radical to which is appended an aryl group. The arylalkenyl groups of this invention can be optionally substituted.
The term xe2x80x9carylalkenyloxycarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R68xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R68 is an arylalkenyl group. The arylalkenyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to an alkoxy group to which is attached an aryl group. The arylalkoxy groups of this invention can be optionally substituted.
The term xe2x80x9carylalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an aryl group. Representative arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like. The arylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9carylalkylcarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an arylalkylcarbonyloxy group (i.e., R62C(O)Oxe2x80x94 wherein R62 is an arylalkyl group). The arylalkylcarbonyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to an aryl group attached to the parent molecular group through an oxygen atom. The aryloxy groups of this invention can be optionally substituted.
The term xe2x80x9caryloxycarbonylxe2x80x9d as used herein refers to an aryloxy group attached to the parent molecular group through a carbonyl group. The aryloxycarbonyl groups of this invention can be optionally substituted.
The term xe2x80x9caryloylxe2x80x9d as used herein refers to an aryl group attached to the parent molecular group through a carbonyl group. The aryloyl groups of this invention can be optionally substituted.
The term xe2x80x9carylalkyloxycarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R67xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R67 is an arylalkyl group. The arylalkyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9caryloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R65xe2x80x94Oxe2x80x94 wherein R65 is an aryl group. The aryloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9carylalkoxyxe2x80x9d as used herein refers to an alkoxy radical to which is appended R65xe2x80x94Oxe2x80x94 wherein R65 is an aryl group. The arylalkoxy groups of this invention can be optionally substituted.
The term xe2x80x9carylalkyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an arylalkoxy group. The arylalkyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9caryloxyxe2x80x9d as used herein refers to R65xe2x80x94Oxe2x80x94 wherein R65 is an aryl group. The aryloxy groups of this invention can be optionally substituted. The aryloxy groups of this invention can be optionally substituted.
The term xe2x80x9c(aryl)oylxe2x80x9d as used herein refers to an aryl group attached to the parent molecular group through a carbonyl group. The (aryl)oyl groups of this invention can be optionally substituted.
The term xe2x80x9caryloxythioalkoxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R75xe2x80x94Sxe2x80x94 wherein R75 is an aryloxyalkyl group. The aryloxythioalkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9caryloxycarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R65xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R65 is an aryl group. The aryloxycarbonyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9carylsulfonylxe2x80x9d as used herein refers to R36S(O)2xe2x80x94 wherein R36 is an aryl group. The arylsulfonyl groups of this invention can be optionally substituted.
The term xe2x80x9carylsulfonyloxyxe2x80x9d as used herein refers to R37S(O)2Oxe2x80x94 wherein R37 is an aryl group. The arylsulfonyloxy groups of this invention can be optionally substituted. The term xe2x80x9ccarboxyxe2x80x9d as used herein refers to xe2x80x94COOH.
The term xe2x80x9ccarboxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a carboxy (xe2x80x94COOH) group. The carboxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9ccyanoalkylxe2x80x9d as used herein used herein refers to a loweralkyl radical to which is appended a cyano (xe2x80x94CN) group. The cyanoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9ccarboxaldehydexe2x80x9d as used herein used herein refers to xe2x80x94CHO.
The term xe2x80x9c(carboxaldehyde)alkylxe2x80x9d as used herein used herein refers to a carboxaldehyde group attached to a loweralkyl group. The (carboxaldehyde)alkyl groups of this invention can be optionally substituted.
The terms xe2x80x9ccycloalkanoylxe2x80x9d and xe2x80x9c(cycloalkyl)oylxe2x80x9d refer to a cycloalkyl group attached to the parent molecular group through a carbonyl group. The cycloalkanoyl and (cycloalkyl)oyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkanoylalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a cycloalkanoyl group (i.e., R60xe2x80x94C(O)xe2x80x94 wherein R60 is a cycloalkyl group).
The cycloalkanoylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkylalkoxyalkylxe2x80x9d as used herein refers to an alkoxyalkyl group to which is attached a cycloalkyl group. The cycloalkylalkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkenylxe2x80x9d as used herein refers to an alicyclic group comprising from 3 to 10 carbon atoms and containing a carbon-carbon double bond including, but not limited to, cyclopentenyl, cyclohexenyl and the like. The cycloalkenyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkoxyxe2x80x9d as used herein refers to a cycloalkyl group attached to the parent molecular group through an oxygen atom. The cycloalkoxy groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkoxyalkylxe2x80x9d as used herein refers to a loweralkyl group to which is attached a cycloalkoxy group. The cycloalkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkoxycarbonylxe2x80x9d as used herein refers to a cycloalkoxy group attached to the parent molecular group through a carbonyl group. The cycloalkoxycarbonyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkylxe2x80x9d as used herein refers to an alicyclic group comprising from 3 to 10 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, adamantyl and the like. The cycloalkyl groups of this invention can be optionally substituted. The cycloalkyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkylaminocarbonylxe2x80x9d as used herein refers to NHR60xe2x80x2C(O)xe2x80x94 wherein R60xe2x80x2 is a cycloalkyl group. The cycloalkylaminocarbonyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkylaminothiocarbonylxe2x80x9d as used herein refers to NHR60xe2x80x2C(S)xe2x80x94 wherein R60xe2x80x2 is defined above. The cycloalkylaminothiocarbonyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkylalkoxyxe2x80x9d as used herein refers to an alkoxy radical to which is appended a cycloalkyl group. The cycloalkylalkoxy groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkylalkoxyalkylxe2x80x9d as used herein refers to an alkyl radical to which is appended a cycloalkylalkoxy group. The cycloalkylalkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkylalkoxycarbonylxe2x80x9d as used herein refers to a cycloalkylalkoxy radical attached to the parent molecular group through a carbonyl group. The cycloalkylalkoxycarbonyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkylalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a cycloalkyl group. Representative examples of cycloalkylalkyl include cyclopropylmethyl, cyclohexylmethyl, 2-(cyclopropyl)ethyl, adamantylmethyl and the like. The cycloalkylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9ccycloalkyloxycarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R64xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R64 is a cycloalkyl group. The cycloalkyloxycarbonyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cdialkoxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended two alkoxy groups. The dialkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cdialkylaminoxe2x80x9d as used herein refers to R38R39Nxe2x80x94 wherein R38 and R39 are independently selected from loweralkyl, for example dimethylamino, diethylamino, methyl propylamino, and the like. The dialkylamino groups of this invention can be optionally substituted.
The term xe2x80x9cdialkylaminoalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended a dialkylamino group. The dialkylaminoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cdialkylaminocarbonylalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R73xe2x80x94C(O)xe2x80x94 wherein R73 is a dialkylamino group. The dialkylaminocarbonylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cdioxoalkylxe2x80x9d as used herein refers to a loweralkyl radical which is substituted with two oxo (xe2x95x90O) groups. The dioxoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cdithioalkoxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended two thioalkoxy groups. The dithioalkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d as used herein refers to I, Br, Cl or F.
The term xe2x80x9chaloalkenylxe2x80x9d as used herein refers to an alkenyl radical, as defined above, bearing at least one halogen substituent. The haloalkenyl groups of this invention can be optionally substituted.
The term xe2x80x9chaloalkylxe2x80x9d as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like. Haloalkyl can also include perfluoroalkyl wherein all hydrogens of a loweralkyl group are replaced with fluorides.
The term xe2x80x9cheterocyclic ringxe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d as used herein refers to a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur or a 5-membered ring containing 4 nitrogen atoms; and includes a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms; one oxygen atom; one sulfur atom; one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non-adjacent positions; one oxygen and one sulfur atom in non-adjacent positions; two sulfur atoms in non-adjacent positions; two sulfur atoms in adjacent positions and one nitrogen atom; two adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one sulfur atom; two non-adjacent nitrogen atoms and one oxygen atom. The 5-membered ring has 0-2 double bonds and the 6- and 7-membered rings have 0-3 double bonds. The term xe2x80x9cheterocyclicxe2x80x9d also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring (for example, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl or benzothienyl and the like). Heterocyclics include: pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, pyrimidyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl and benzothienyl. Heterocyclics also include bridged bicyclic groups wherein a monocyclic heterocyclic group is bridged by an alkylene group, for example, 
and the like.
Heterocyclics also include compounds of the formula 
wherein X* is xe2x80x94CH2xe2x80x94, xe2x80x94CH2Oxe2x80x94 or xe2x80x94Oxe2x80x94 and Y* is xe2x80x94C(O)xe2x80x94 or xe2x80x94(C(Rxe2x80x3)2)vxe2x80x94 wherein Rxe2x80x3 is hydrogen or C1-C4-alkyl and v is 1, 2 or 3 such as 1,3-benzodioxolyl, 1,4-benzodioxanyl and the like.
Heterocyclics can be unsubstituted or substituted with one, two, three, four or five substituents independently selected from the group consisting of a) hydroxy, b) xe2x80x94SH, c) halo, d) oxo (xe2x95x90O), e) thioxo (xe2x95x90S), f) amino, g) xe2x80x94NHOH, h) alkylamino, i) dialkylamino, j) alkoxy, k) alkoxyalkoxy, l) haloalkyl, m) hydroxyalkyl, n) alkoxyalkyl, o) cycloalkyl which is unsubstituted or substituted with one, two, three or four loweralkyl groups, p) cycloalkenyl which is unsubstituted or substituted with one, two, three or four loweralkyl groups, q) alkenyl, r) alkynyl, s) aryl, t) arylalkyl, u) xe2x80x94COOH, v) xe2x80x94SO3H, w) loweralkyl, x) alkoxycarbonyl, y) xe2x80x94C(O)NH2, z) xe2x80x94C(S)NH2, aa) xe2x80x94C(xe2x95x90Nxe2x80x94OH)NH2, bb) aryl-L16xe2x80x94C(O)xe2x80x94 wherein L16 is an alkenylene radical, cc) xe2x80x94Sxe2x80x94L17xe2x80x94C(O)OR40 wherein L17 is an alkylene radical which is unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkanoyl, oxo (xe2x95x90O) or methylamino (xe2x95x90CHNR41R42 wherein R41 is hydrogen or loweralkyl and R42 is loweralkyl) and R40 is hydrogen or a carboxy-protecting group, dd) xe2x80x94Sxe2x80x94L18xe2x80x94C(O)NR43R44 wherein L18 is an alkylene radical which is unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkanoyl, oxo (xe2x95x90O) or methylamino (xe2x95x90CHNR41R42 wherein R41 is hydrogen or loweralkyl and R43 and R44 are independently selected from the group consisting of hydrogen, loweralkyl and aryl, ee) xe2x80x94Sxe2x80x94L19xe2x80x94CN wherein L19 is an alkylene radical, ff) xe2x80x94Sxe2x80x94L20xe2x80x94R45 wherein L20 is absent or is an alkylene radical or an alkenylene radical or an alkynylene radical wherein the alkylene, alkenylene or alkynylene radical is unsubstituted or substituted with oxo (xe2x95x90O) and R45 is hydrogen, aryl, arylalkyl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, gg) xe2x80x94Oxe2x80x94L21xe2x80x94R46 wherein L21 is absent or is an alkylene radical or an alkenylene radical or an alkynylene radical wherein the alkylene, alkenylene or alkynylene radical is unsubstituted or substituted with one or two substituents independently selected from the group consisting of alkanoyl, oxo (xe2x95x90O) or methylamino (xe2x95x90CHNR41R42 wherein R41 is hydrogen or loweralkyl and R46 is hydrogen, aryl, arylalkyl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, hh) xe2x80x94Oxe2x80x94S(O)2xe2x80x94R47 wherein R47 is aryl, arylalkyl, heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, ii) xe2x80x94S(O)2xe2x80x94NHxe2x80x94R48 wherein R48 is aryl, arylalkyl, heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, jj) alkylsulfinyl, kk) alkylsulfonyl, ll) arylsulfonyl, mm) arylsulfonyloxy, nn) xe2x80x94C(xe2x95x90NOR49)C(O)OR50 wherein R49 is hydrogen or loweralkyl and R50 is hydrogen or a carboxy-protecting group, oo) alkoxycarbonylalkyl, pp) carboxyalkyl, qq) cyanoalkyl, rr) alkylaminoalkyl, ss) N-protected alkylaminoalkyl, tt) dialkylaminoalkyl, uu) dioxoalkyl, vv) loweralkyl-C(O)xe2x80x94, ww) loweralkyl-C(S)xe2x80x94, xx) aryl-C(O)xe2x80x94, yy) aryl-C(S)xe2x80x94, zz) loweralkyl-C(O)xe2x80x94Oxe2x80x94, aaa) loweralkyl-Sxe2x80x94C(S)xe2x80x94 bbb) N-protected amino, ccc) aminoalkyl-C(O)xe2x80x94, ddd) N-protected aminoalkyl-C(O)xe2x80x94 eee) aminoalkyl-C(S)xe2x80x94, fff) N-protected aminoalkyl-C(S)xe2x80x94, ggg) aminoalkyl, hhh) N-protected aminoalkyl, iii) formyl, jjj) cyano, kkk) nitro, lll) spiroalkyl, mmm) oxoalkyloxy, nnn) R53xe2x80x94L22xe2x80x94, wherein L22 is alkenylene or alkynylene and R53 is aryl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, ooo) aryl-NHxe2x80x94C(O)xe2x80x94, ppp) R54xe2x80x94Nxe2x95x90Nxe2x80x94 wherein R54 is aryl or heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, qqq) xe2x95x90Nxe2x80x94R55 wherein R55 is hydrogen, aryl, heterocyclic, xe2x80x94S(O)2-aryl or xe2x80x94S(O)2-heterocyclic wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, rrr) diarylalkyl-Nxe2x95x90Nxe2x80x94, sss) aryl-N(R56)xe2x80x94 or arylalkyl-N(R56)xe2x80x94 wherein R56 is hydrogen or an N-protecting group, ttt) arylsulfonylalkyl, uuu) heterocyclicsulfonylalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, vvv) xe2x95x90C(CN)(C(O)NH2), www) xe2x95x90C(CN)(C(O)O-loweralkyl), xxx) heterocyclic or heterocyclicalkyl wherein the heterocyclic is unsubstituted or substituted with one, two or three substituents independently selected from the group consisting of loweralkyl, hydroxy, hydroxyalkyl, halo, nitro, oxo (xe2x95x90O), amino, N-protected amino, alkoxy, thioalkoxy and haloalkyl, yyy) hydroxythioalkoxy, zzz) aryloxyalkyl, aaaa) aryloxyalkylthioalkoxy, bbbb) dialkoxyalkyl, cccc) dithioalkoxyalkyl, dddd) arylalkyl-NHxe2x80x94L23xe2x80x94 wherein L is an alkylene group, eeee) heterocyclicalkyl-NHxe2x80x94L24xe2x80x94 wherein L24 is an alkylene group, ffff) aryl-S(O)2xe2x80x94NHxe2x80x94L25xe2x80x94 wherein L25 is an alkylene group, gggg) heterocyclicxe2x80x94S(O)2xe2x80x94NHxe2x80x94L26xe2x80x94 wherein L26 is an alkylene group, hhhh) aryl-C(O)xe2x80x94NHxe2x80x94L27xe2x80x94 wherein L is an alkylene group and iiii) heterocyclicxe2x80x94C(O)xe2x80x94NHxe2x80x94L28xe2x80x94 wherein L28 is an alkylene group, jjjj) Ryy(CH2)nxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94(CH2)m wherein Ryy is cycloalkyl, aryl and loweralkyl, n and m are independently 0-2, Z is O or absent, Y is absent, CH2, CHOH or C(O), with the proviso that when X is O, Z is absent and with the proviso that when Z is O, X is absent and with the proviso that when Y is CHOH, X and Z are absent.
The term xe2x80x9c(heterocyclic)alkoxyxe2x80x9d as used herein refers to an alkoxy group to which is attached a heterocycle. The (heterocyclic)alkoxy groups of this invention can be optionally substituted.
The term xe2x80x9c(heterocyclic)alkylxe2x80x9d as used herein refers to a heterocyclic group as defined above appended to a loweralkyl radical as defined above. Examples of heterocyclic alkyl include 2-pyridylmethyl, 4-pyridylmethyl, 4-quinolinylmethyl and the like. The (heterocyclic)alkyl groups of this invention can be optionally substituted.
The term xe2x80x9c(heterocyclic)oxyxe2x80x9d as used herein refers to a heterocycle connected to the parent molecular group through an oxygen atom. The (heterocyclic)oxy groups of this invention can be optionally substituted.
The term xe2x80x9c(heterocyclic)oxyalkylxe2x80x9d as used herein refers to a loweralkyl group to which is attached a (heterocyclic)oxy group. The (heterocyclic)oxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9c(heterocyclic)alkoxyalkylxe2x80x9d as used herein refers to an alkoxyalkyl group to which is attached a heterocycle. The (heterocyclic)alkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cheterocycliccarbonyloxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended R72xe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein R72 is a heterocyclic group. The heterocycliccarbonyloxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9chydroxyxe2x80x9d as used herein refers to xe2x80x94OH.
The term xe2x80x9chydroxyalkylxe2x80x9d as used herein refers to a loweralkyl radical to which is appended an hydroxy group. The hydroxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9chydroxyarylalkylxe2x80x9d as used herein refers to a arylalkyl group to which is appended a hydroxy group. The hydroxyarylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9chydroxythioalkoxyxe2x80x9d as used herein refers to R51Sxe2x80x94 wherein R51 is a hydroxyalkyl group. The hydroxythioalkoxy groups of this invention can be optionally substituted.
The term xe2x80x9cloweralkylxe2x80x9d as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like. The loweralkyl groups of this invention can be optionally substituted.
The term xe2x80x9cN-protected alkylaminoalkylxe2x80x9d as used herein refers to an alkylaminoalkyl group wherein the nitrogen is N-protected. The N-protected alkylaminoalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cnitroxe2x80x9d as used herein refers to xe2x80x94NO2.
The term xe2x80x9coxoxe2x80x9d as used herein refers to (xe2x95x90O).
The term xe2x80x9coxoalkyloxyxe2x80x9d as used herein refers to an alkoxy radical wherein the loweralkyl moiety is substituted with an oxo (xe2x95x90O) group. The oxoalkyloxy groups of this invention can be optionally substituted.
The term oxyamino(alkyl)carbonylalkyl as used herein refers to.
The term oxyamino(arylalkyl)carbonylalkyl as used herein refers to.
The term oxyaminocarbonylalkyl as used herein refers to.
The term xe2x80x9cspiroalkylxe2x80x9d as used herein refers to an alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group. The spiroalkyl groups of this invention can be optionally substituted.
The term xe2x80x9csulfhydrylxe2x80x9d as used herein refers to xe2x80x94SH.
The term xe2x80x9csulfhydrylalkylxe2x80x9d as used herein refers to a loweralkyl group to which is attached a sulfhydryl group. The sulfhydrylalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cthioalkoxyxe2x80x9d as used herein refers to R52Sxe2x80x94 wherein R52 is loweralkyl. Examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and the like. The thioalkoxy groups of this invention can be optionally substituted.
The term xe2x80x9cthioalkoxyalkylxe2x80x9d as used herein refers to a thioalkoxy group as previously defined appended to a loweralkyl group as previously defined. Examples of thioalkoxyalkyl include thiomethoxymethyl, 2-thiomethoxyethyl and the like. The thioalkoxyalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cthiocycloalkoxyxe2x80x9d as used herein refers to a cycloalkyl group attached to the parent molecular group through a sulfur atom. The thiocycloalkoxy groups of this invention can be optionally substituted.
The term xe2x80x9cthiocycloalkoxyalkylxe2x80x9d as used herein refers to a loweralkyl group to which is attached a thiocycloalkoxy group. The thiocycloalkoxyalkyl groups of this invention can be optionally substituted.
Preferred compounds of the invention are compounds of formula I wherein R1 is unsubstituted or substituted phenyl and R2 is xe2x80x94C(O)NHxe2x80x94CH(R14)xe2x80x94C(O)OR15 or xe2x80x94C(O)NHxe2x80x94CH(R14)xe2x80x94C(O)NHSO2R16 wherein L2, R14 R15 and R16 are defined above.
More preferred compounds of the invention are compounds of formula I wherein R1 is unsubstituted or substituted phenyl and R2 is 
Still more preferred compounds have formula I wherein R3 is selected from the group consisting of (a) pyridyl, (b) imidazolyl, and (c) furyl wherein the pyridyl, imidazolyl, or furyl group may be substituted with 1, 2 or 3 substituents selected from the group consisting of aryl, loweralkyl, halo, nitro, haloalkyl, hydroxy, hydroxyalkyl, amino, N-protected amino, alkoxy, and thioalkoxy.
Still more preferred compounds of the invention have the structure defined immediately above wherein R1 is unsubstituted or substituted phenyl and R2 is 
The most preferred compounds have the structure defined immediately above wherein R3 is unsubstituted or substituted pyridyl or imidazolyl.
The ability of the compounds of the invention to inhibit protein farnesyltransferase or protein geranylgeranyltransferase can be measured according to the method of Moores, et al., J. Biol. Chem. 266: 14603 (1991) or the method of Vogt, et al., J. Biol. Chem. 270:660-664 (1995). In addition, procedures for determination of the inhibition of farnesylation of the oncogene protein Ras are described by Goldstein, et al., J. Biol. Chem., 266:15575-15578 (1991) and by Singh in U.S. Pat. No. 5,245,061.
In addition, in vitro inhibition of protein farnesyltransferase may be measured by the following procedure. Rat brain protein farnesyltransferase activity is measured using an Amersham Life Science commercial scintillation proximity assay kit and substituting a biotin-K Ras B fragment (biotin-Lys-Lys-Ser-Lys-Thr-Lys-Cys-Val-Ue-Met-CO2H), 0.1 mM final concentration, for the biotin-lamin substrate provided by Amersham. The enzyme is purified according to Reiss, Y., et al., Cell, 62: 81-88 (1990), utilizing steps one through three. The specific activity of the enzyme is approximately 10 mmol substrate farnesylated/mg enzyme/hour. The percent inhibition of the farnesylation caused by the compounds of the invention (at 10xc3x9710xe2x88x926 M) compared to an uninhibited control sample is evaluated in the same Amersham test system.
The % inhibition of protein farnesyltransferase was determined for representative compounds of the invention. The results are summarized in Table 1.
Additional methods for the measurement of in vitro inhibition of protein prenylation (i.e., inhibition of farnesyltransferase or geranylgeranyltransferase) are described below.
Assays are performed using the glass fiber filter binding assay procedure with either rabbit reticulocyte lysate or Frase or GGTase I fractions isolated from bovine brains using a combination of hydrophobic and DEAE column chromatography procedures. Protein substrates are purchased from Panvera Corporation (H-ras for FTase, H-ras-CVLL for GGTase I). Tritium labeled prenyl lipid substrates (FPP or GGPP) are obtained from Amersham Life Science.
FTase
3H-Farnesyldiphosphate (final concentration 0.6 xcexcM), H-Ras (final concentration 5.0 xcexcM) and the test compound (various final concentrations from a stock solution in 50% DMSO/water; final concentration DMSO  less than 2%) were mixed in buffer (50 mM HEPES (pH 7.5), 30 mM MgCl2, 20 mM KCl, 10 xcexcM ZnCl2, 5 mM DTT, 0.01% Triton X-100) to give a final volume of 50 xcexcL. The mixture was brought to 37xc2x0 C., enzyme was added, and the reaction is incubated for 30 minutes. 1 mL of 1 M HCl/ethanol was added to stop the reaction, and the mixture was allowed to stand for 15 minutes at room temperature then diluted with 2 mL of ethanol. The reaction mixture was filtered through a 2.5 cm glass microfiber filter from Whatman and washed with four 2 mL portions of ethanol. The glass filter was transferred to a scintillation vial and 5 mL of scintillation fluid was added. The radioisotope retained on the glass fiber filter was counted to reflect the activity of the enzymes. The IC50 value was calculated by measuring the activity of the enzyme over a suitable range of inhibitor concentrations.
GGTase I
3H-geranylgeranyldiphosphate (final concentration 0.5 xcexcM), H-Ras-CVLL (final concentration 5.0 xcexcM) and the test compound (various final concentrations from a stock solution in 1:1 DMSO/water; final concentration DMSO  less than 2%) were mixed in buffer (50 mM Tris-HCl (pH 7.2), 30 mM MgCl2, 20 mM KCl, 10 xcexcM ZnCl2, 5 mM DTT, 0.01% Triton X-100) to give a final volume of 50 xcexcL. The mixture was brought to 37xc2x0 C., treated with enzyme, and incubated for 30 minutes. 1 mL of 1 M HCl/ethanol was added to stop the reaction, and the mixture was allowed to stand for 15 minutes at room temperature then diluted with 2 mL of ethanol. The reaction mixture was filtered through a 2.5 cm glass microfiber filter from Whatman and washed with four 2 mL portions of ethanol. The glass filter was transferred to a scintillation vial, and 5 mL scintillation fluid was added. The radioisotope retained on the glass fiber filter was counted to reflect the activity of the enzymes. The IC50 value was calculated by measuring the activity of the enzyme over a suitable range of inhibitor concentrations.
Additionally, the ability of the compounds of the invention to inhibit prenylation in whole cells, inhibit anchorage-independent tumor cell growth and inhibit human tumor xenograft in mice could be demonstrated according to the methods described in PCT Patent Application No. WO95/25086, published Sep. 21, 1995, which is hereby incorporated herein by reference.
The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. These salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, parnoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl halides (such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides), dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of the compounds of formula (I)-(XII) or separately by reacting the carboxylic acid function with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Such pharmaceutically acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like as well as nontoxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. Other representative organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
The compounds of the invention are useful (in humans and other mammals) for inhibiting protein isoprenyltransferases (i.e, protein farnesyltransferase and/or protein geranylgeranyltransferase) and the isoprenylation (i.e., farnesylation and/or geranylgeranylation) of Ras. These inhibitors of protein isoprenyltransferases are also useful for inhibiting or treating cancer in humans and other mammals. Examples of cancers which may be treated with the compounds of the invention include, but are not limited to, carcinomas such as lung, colorectal, bladder, breast, kidney, ovarian, liver, exocrine pancreatic, cervical, esophageal, stomach and small intestinal; sarcomas such as oesteroma, osteosarcoma, lepoma, liposarcoma, hemanioma and hemangiosarcoma; melanomas such as amelanotic and melanotic; mixed types of cancers such as carcinosarcoma, lymphoid tissue type, follicular reticulum, cell sarcoma and Hodgkins disease and leukemias, such as myeloid, acute lymphoblastic, chronic lymphocytic, acute myloblastic and chronic mylocytic.
The ability of the compounds of the invention to inhibit or treat cancer can be demonstrated according to the methods of Mazerska Z., Woynarowska B., Stefanska B., Borowski S., Drugs Exptl. Clin. Res. 13(6), 345-351 (1987) Bissery, M. C., Guenard F., Guerritte-Voegelein F., Lavelle F., Cancer Res. 51, 4845-4852 (1991) and Rygaard J., and Povlsen C., Acta Pathol. Microbiol. Scand. 77, 758 (1969), which are hereby incorporated herein by reference.
These inhibitors of protein isoprenyltransferases are also useful for treating or preventing restenosis in humans and other mammals. The ability of the compounds of the invention to treat or prevent restenosis can be demonstrated according to the methods described by Kranzhofer, R. et al. Circ. Res. 73: 264-268 (1993), Mitsuka, M. et al. Circ. Res. 73: 269-275 (1993) and Santoian, E. C. et al. Circulation 88: 11-14 (1993), which are hereby incorporated herein by reference.
For use as a chemotherapeutic agent, the total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.01 to 500 mg/kg body weight daily, preferably in amounts from 0.1 to 20 mg/kg body weight daily and more preferably in amounts from 0.5 to 10 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
For treatment or prevention of restenosis, the total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 1000 mg/kg body weight daily and more preferred from 1.0 to 50 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques.
Injectable preparations, for example sterile injectable aqueous or oleagenous suspensions, may be formulated according to the known art using suitable dispersing or wetting and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent (as in a solution in 1,3-propanediol, for example). Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid find use in the preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. These dosage forms may also comprise additional substances other than inert diluents such as lubricating agents like magnesium stearate. With capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills may also be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. Such compositions may also comprise adjuvants such as wetting agents, emulsifying and suspending agents and sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically aceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq., which is hereby incorporated herein by reference.
While the compounds of the invention can be administered as the sole active pharmaceutical agent for the treatment of cancer, they can also be used in combination with one or more other chemotherapeutic agents.
Representative examples of chemotherapeutic agents are described in Holleb, et al., Clinical Oncology, American Cancer Society, United States (1991) p 56 et seq., which is hereby incorporated herein by reference These agents include alkylating agents such as the nitrogen mustards (mechloethamine, melphalan, chlorambucil, cyclophosphamide and ifosfamide), nitrosoureas (carmustine, lomustine, semustine, streptozocin), alkyl sulfonates (busulfan), triazines (dacarbazine) and ethyenimines (thiotepa, hexamethylmelamine); folic acid analogues (methotrexate); pyrimidine analogues (5-fluorouracil, cytosine arabinoside); purine analogues (6-mercaptopurine, 6-thioguanine); antitumor antibiotics (actinomycin D, the anthracyclines (doxorubicin), bleomycin, mitomycin C, methramycin); plant alkaloids such as vinca alkaloids (vincristine and vinblastine) and etoposide (VP-16); hormones and hormone antagonists (tamoxifen and corticosteroids); and miscellaneous agents (cisplatin, taxol and brequinar).
The above compounds to be employed in combination with the isoprenyl protein transferase inhibitor of the invention will be used in therapeutic amounts as indicated in the Physicians"" Desk Reference (PDR) 47th Edition (1993), which is incorporated herein by reference or by such therapeutically useful amounts as would be known to one of ordinary skill in the art.
The compounds of the invention and the other chemotherapeutic agent can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied to obtain a desired therapeutic response depending on the route of administration, severity of the disease and the response of the patient.
When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.
In general, the compounds of the invention can be prepared by the processes illustrated in the following Schemes 1-16. In these general schemes compounds of the formula I are used to exemplify the methods, but the methods are intended to be applicable to all of the compounds of the invention. 
Scheme 16 illustrates an alternative method for preparing compounds wherein R2 is xe2x80x94C(O)NHxe2x80x94CH(R14)xe2x80x94C(O)OR15 or 
as defined above. 